PNH Overview

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired disease, characterised by intravascular haemolysis, thrombosis and is associated with bone marrow failure. PNH occurs due to a clonal expansion of abnormal haematopoietic cells that are exquisitely sensitive to the uncontrolled activity of terminal complement. In its most severe form PNH leads to severe anaemia with patients frequently being transfusion dependent for many years (if not indefinitely). In addition to the anaemia, patients suffer from the direct effects of intravascular haemolysis that results in the absorption of nitric oxide, a key molecule in homeostasis, leading to smooth muscle dysfunction, platelet activation and other consequences. This often results in severe disabling abdominal pain, dysphagia, profound lethargy and, in men, erectile dysfunction. It can also contribute to many of the complications seen in PNH such as thromboses, renal impairment and raised pulmonary pressures.

Approximately half of patients suffer from thrombosis, often in major vessels, and historically a third of patients die as a direct result of thrombotic complications. In addition, the haemolysis in PNH results in renal impairment in over half of patients and approximately half of patients develop raised pulmonary pressures.

PNH can occur at any age and in most patients will persist for the remainder of the patient’s life. Approximately half of patients with PNH die as a direct result of their disease, many others are transfusion-dependent for decades and for most patients with haemolytic PNH the disease has a major impact on the patient’s quality of life. Pregnancy is extremely high risk in PNH with reported maternal mortalities of up to 20%, predominantly resulting from thrombotic complications, and reports of a high incidence of foetal loss.

Most of the observed symptoms and complications are due to the uncontrolled activity of complement on the abnormal PNH cells. Eculizumab is a monoclonal antibody that blocks the activation of terminal complement and was approved for the treatment of PNH in 2007. Eculizumab stops intravascular haemolysis in PNH rendering most patients transfusion independent whilst causing a dramatic improvement in quality of life. In addition, eculizumab stabilises or improves renal function, prevents the occurrence of thrombotic complications and reduces the risk of pulmonary hypertension. Recent data demonstrates that eculizumab both prevents most of the complications of PNH and significantly improves survival.

For more information visit the PNH National Service website

Eculizumab

Eculizumab (or Soliris) is an intravenous infusion that is administered every 2 weeks in the long-term. Eculizumab blocks the activation of complement and therefore protects the PNH cells from destruction or stimulation. As soon as eculizumab therapy is stopped, complement will become active and the PNH cells that were previously protected will be vulnerable to complement attack again. It is therefore usual that eculizumab is a treatment that needs to be given lifelong.

Eculizumab has been proven to reduce the symptoms experienced in PNH and has been shown to improve people’s quality of life. It also reduces the risks of many of the complications of PNH, such as thrombosis, renal failure or pulmonary hypertension (high blood pressure in the lungs). It has also therefore improved life expectancy in certain groups of patients with PNH.

Blood Transfusions

Anaemia is one of the commonest symptoms of PNH. Blood transfusions are an important therapy as they can alleviate some of the symptoms experienced. We generally only use transfusions if the patient has symp-
toms of anaemia.

Folic Acid

Folic acid is a vitamin needed by the bone marrow to help make blood cells. In PNH, the bone marrow often produces more red blood cells than normal to try to compensate for the blood cells being destroyed in the bloodstream. Taking folic acid tablets helps to ensure that the bone marrow has enough folic acid to make blood cells.

Anticoagulation

Some patients are on blood thinning medication, such as warfarin, to reduce the risk of developing blood clots. These medications make people more likely to bruise and bleed.

Iron supplements and iron removal

Iron levels may be either too low or too high in PNH, usually depending on whether the patient is on specific treatment for the PNH or not. Some patients therefore may require iron supplements and others may need medication to reduce the iron levels in the body.

Prevention of meningococcal infection: vaccination and antibiotics

Individuals treated with eculizumab are at increased risk of infection by a specific bacterium (Neisseria Meningitidis). Both vaccination against Neisseria Meningitidis and preventative antibiotics are used to reduce this potential risk.

Allogeneic Bone Marrow Transplantation

Bone marrow transplant is the only curative treatment for PNH but has many significant complications which may occur in some patients. It is not very common for this to be recommended for patients with PNH unless there is severe bone marrow failure co-existing with PNH.

Monklands Outreach Clinic

PNH Scotland is a relatively new charity, registered in November 2011. The charity’s objectives are to raise awareness of PNH and to ensure all patients have access to the relevant treatment they need. The aim is to provide a point of contact for patients and their families to make sure those affected by PNH do not feel isolated or unsure of the condition.

The PNH Scotland patient group meets every three months in Monklands hospital at the PNH outreach clinic. It is an opportunity for patients and family members to chat, laugh and share advice.

Patient perspectives

In 2005 I started to feel very run down with constant colds, sore throats and headaches. I ignored them for a few months but eventually had to go to my GP, I was so tired and I ached all over. My eyes hurt to be open and I had constant, severe headaches.

After a few months of tests, my GP referred me to a consultant haematologist. This was the start of a long and difficult journey towards diagnosis. After 11?2 years attending the haematologist, undergoing countless tests and receiving several wrong diagnoses, I was no further forward. Each test raised my hopes that I would finally find out what was wrong with me. I would anxiously await the results and feel total desperation with every negative result. Harder though were the times when I was told the tests were positive only to find out a few weeks later that they were wrong and that we would have to start all over again. These months were the hardest and most stressful of any in my illness.

Eventually I was fortunate enough to be seen by a young Registrar who was on his 6 weeks rotation. He asked me all the usual questions and then said’ “I think I know what’s wrong with you”. After 11?2 years I didn’t hold out much hope. When I went back for the results he said, “I was right, you have Paroxysmal Nocturnal Haemoglobinuria or PNH”. The Registrar had studied with a doctor who now worked with a world-renowned PNH specialist. I was in the right place at the right time to just happen to meet someone who knew about PNH and who knew where there was an expert. The following week that Registrar moved on.

On my diagnosis day, I was told there wasn’t much known about the condition and I would on average get 10 years of life. The diagnosis was not great but it was such a relief to finally know what I had. Not knowing was far worse than anything the doctor could have told me.

During the next year I was surviving on blood transfusions. The transfusions didn’t help with my quality of life and were in fact very tiring. They also didn’t protect me from the risk of a fatal blood clot; they merely stopped my blood levels falling dangerously low. We were told about a drug, called Soliris. It is not a cure for PNH but it can give patients an improved quality of life. The drug is extremely expensive and is not funded in Scotland so I was told I was unlikely to get it. It was heart-breaking knowing there was a drug that could give me my life back but I could not get access to it. Over the next year though, I started to reject my blood transfusions and it may sound strange, but this was very fortunate! As I would not have survived without transfusions, the Scottish Government thankfully agreed to fund me for the drug. I started Soliris in May 2008.

Within 6 months I started to feel able to do a lot more and since then I have gradually got stronger. The latest research shows that Soliris not only gives a better quality of life but it restores a patient’s life expectancy to normal.

Now a nurse visits me in my home every 2 weeks to give me my IV infusion, and I go and see one of the PNH Consultants at their outreach clinic at Monklands Hospital once every 12 weeks. I know that if I have any problems I can contact the team in Leeds 24 hours a day.

Once I was strong enough, I was asked to set up a Scottish PNH patient group. We held our first patient group at the start of 2012 where I got to meet my fellow PNH patients. They told me of their feelings of isolation, their exhaustion, and their fights to get funding for the drug and their fears for the future. The patient group, PNH Scotland, is now a fully registered charity with the aim to raise awareness of PNH, help provide information for newly diagnosed patients and ensure drug funding for those deemed to need it.

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After a year of investigations, I was diagnosed with PNH in 2008, aged 23. The day I was diagnosed I did the first (and worst) thing we all do when we are diagnosed with an illness we have never heard of – I Googled it. Big mistake. I came across the very outdated, and incredibly frightening ‘life expectancy’ figure of ten years after diagnosis. I’m glad to say with modern medical technology this is no longer the case.

In a way, I was very lucky with my PNH, although my Clone level was slowly increasing (from 40% to around 90% over three years) I didn’t really feel that bad. I could still ride horses, go on ski holidays and work full-time. Unlike most other patients with my clone level and blood counts, I didn’t need blood transfusions. My haematology team couldn’t really understand this, but we all took it as a blessing.

In person and on paper I was two different people. They said I really should be almost house-bound, with little to no energy, not living the life I was. However, over time I did start to feel the effects of my PNH Disease, but not to the same extent as other people with my clone level (I was starting to struggle with energy levels which was starting to affect my mental well-being). Due to the risk of blood clots associated with my Clone level, and my symptoms progressing, the Leeds team made the decision to put me on Eculizumab therapy in 2013. The difference was instant. My colleagues noticed how much more energy I had and I became more confident, it made life so much easier.

What causes PNH?

It is not fully understood why people develop PNH. Inside the bone marrow, blood cells are made by stem cells (the seed cells of the marrow). PNH occurs due to a change (or mutation) in a gene in one of the stem cells in the bone marrow. This mutation happens in a gene called PIG-A and the cells made by this stem cell lack certain proteins on their surface making them ‘weaker’ than normal blood cells. The mutation is “acquired” meaning that it develops in the bone marrow stem cell whilst it is multiplying but is not present from birth. We have evidence that almost all people in the population will develop a PNH mutation at some time but as the resulting PNH cells are weak they rarely grow to a level that they can be routinely detected. Normal blood cells have proteins on the surface that protect the cells from part of the immune system. PNH cells don’t have these protective proteins, which is what makes them ‘weaker’ and causes them to be either destroyed (red cell haemolysis) or activated or stimulated (white blood cells and platelets).

Who gets PNH?

PNH is an extremely rare condition and is thought to affect around 16 people per million in the United Kingdom. It is not an inherited condition, meaning it cannot be passed on from parents to children. Equally, you cannot catch PNH from someone who has it. It can occur at any age. Men and women are affected equally.

PNH and bone marrow failure

PNH is associated with other blood conditions, particularly Aplastic Anaemia (AA) and Myelodysplasia (MDS). Both AA and MDS are types of bone marrow failure meaning the bone marrow is unable to make blood cells normally. In AA, the bone marrow cells look normal but there are just too few present to make enough blood cells whereas in MDS the marrow cells look abnormal and cannot make blood efficiently. In AA and MDS, patients usually have reduced levels of platelets, red and white blood cells. These are the different blood cells normally produced in the bone marrow. Treatment for patients with PNH may be directed at the bone marrow failure as well as PNH itself.

The function of the bone marrow

The main purpose of the bone marrow is to produce blood cells. There are three main types of blood cells made by the bone marrow: red blood cells, white blood cells and platelets.

• Red blood cells carry oxygen around the body as they contain haemoglobin which binds and transports oxygen. Anaemia is where the level of red cells, and therefore the haemoglobin, is low. The symptoms of anaemia include tiredness, palpitations, breathlessness and looking pale.
• White blood cells are responsible for fighting infections and a low white cell count can mean people are more prone to develop infections.
• Platelets are blood cells involved in blood clotting. Low platelet counts are associated with increased bruising and bleeding. Activated (or stimulated) platelets can clump together in the wrong place leading to the formation of blood clots (also known as thromboses).

Why PNH?

PNH was named a long time ago after a description of the symptoms observed in patients. However, the name does not fit for all people who have PNH. “Paroxysmal” refers to symptoms occurring intermittently, “haemoglobinuria” to haemoglobin seen in urine (discolouring it dark red or black urine) and “nocturnal” to it occurring at night (or usually first thing in the morning). In reality the condition is present all the time and not everyone experiences dark urine.

Symptoms

There can be a marked variation in the signs and symptoms observed due to PNH both between patients and in the same patient at different times. Some people exhibit no symptoms whereas others may be affected by a number of very different disease symptoms and complications. Patients with no or few symptoms can still sometimes suffer from complications. These can dramatically affect people’s everyday lives and without treatment some of them can be life threatening. Over time the symptoms experienced by anyone with PNH can change. In some people, symptoms occur all the time and in others only when an episode of haemolysis is experienced. Some of the more common symptoms are listed below:

• Haemoglobinuria – Dark or black urine due to free haemoglobin in the urine. This occurs due to the destruction of red blood cells (haemolysis) that occurs in the circulation so that the red cells effectively burst. This leads to the release of haemoglobin, that is usually packaged inside the red cells, into the plasma (the liquid part of the blood) and this then overflows through the kidneys into the urine. Haemoglobinuria can be confused with haematuria (bleeding into the urine) which often leads to some patients having investigation to look for bleeding.
• Anaemia – Anaemia occurs commonly in PNH due to the constant destruction of red blood cells. It can also be aggravated by bone marrow failure which co-exists in some patients with PNH. Anaemia in turn causes increased tiredness, fatigue and breathlessness.
• Breathlessness – This is in part due to anaemia but can also be experienced due to increased blood pressure in the lungs (pulmonary hypertension) that may occur in PNH. If breathlessness occurs suddenly then it is important to exclude other causes such as infection or blood clots going to the lungs. These are rare but important alternative explanations.
• Difficulty swallowing and abdominal pain – As PNH red blood cells are destroyed, their contents, particularly the haemoglobin, are released into the circulation. Haemoglobin is not meant to be free in the plasma as it binds other gases as well as oxygen. One of these, called nitric oxide, is used by the body to help the muscles of the intestine (amongst other muscles) to work properly. If there is free haemoglobin in the plasma and therefore a low level of nitric oxide this leads to spasm in the muscles of the intestinal/digestive system. This can affect the oesophagus (gullet) causing difficulty swallowing and/or the intestines causing abdominal pain. Occasionally, the abdominal pain is due to a blood clot and this will also need investigations for exclusion.
• Erectile dysfunction – Around half of men with PNH are affected by erectile dysfunction. This also appears to be due to the depletion of nitric oxide by free haemoglobin and is generally worse during an attack of haemoglobinuria.
• Fatigue – Fatigue and tiredness are very common in PNH. Fatigue is something that is difficult to quantify but can be extremely debilitating meaning that some patients at times cannot even manage very mild activity. This is also possibly a symptom of nitric oxide depletion and can occur even when the haemoglobin level is relatively good.
• Jaundice – Yellow discolouration of the sclera (whites of the eye) and the skin due to the continued destruction of red blood cells. The yellow colour is due a substance called bilirubin which is a breakdown product of haemoglobin and is usually processed by the liver. When the level of haemolyis is very high the liver has difficulty processing the bilirubin quickly enough leading to jaundice.
• Kidney damage – This can vary from those mildly affected to kidney failure requiring dialysis treatment (this severity is very rare). The kidney problems in PNH can occur due to the haemolysis, blood clots as well as due to other therapies that might be necessary to treat associated conditions such as aplastic anaemia. Most patients with PNH do not develop significant kidney problems but this needs to be carefully monitored. Occasionally, during an episode of severe haemolysis and haemoglobinuria the kidneys have difficult dealing with the haemoglobin that they are filtering and this can cause a sudden (acute), but usually temporary, kidney failure. It is important during episodes of haemoglobinuria that patients drink plenty of fluid to keep the kidneys well hydrated and to reduce the risk of acute kidney problems.
• Blood clots – Blood clots (thromboses) are a common complication of PNH occurring in up to half of patients. Thrombosis is something we are always keen to exclude as if they occur they need specific treatment and may be serious or even life-threatening. The symptoms of thrombosis are highly variable and depend largely on where they develop and it’s extent. Clots can occur anywhere including in unusual places such as in the veins of the liver and around the brain.

Pregnancy & Contraception

• Contraception – The safest methods of contraception are either the use of progesterone-implanted coils (like the Mirena coil) or using a barrier contraception (i.e. condoms). The combined oral contraceptive pill should ideally be avoided as it can increase the risk of developing a blood clot.
• Fertility – Neither men nor women with PNH have reduced fertility specifically due to their disease. PNH is not an inherited disorder and there is no additional risk of the baby developing PNH. The major risk to the unborn baby is if the mother with PNH becomes unwell during pregnancy. It is therefore critical to closely manage pregnancy in women with PNH to prevent any potential complications (see below).
• Pregnancy – Pregnancy is associated with an increased risk of complications in PNH. In rare cases it may be that pregnancy is not advisable but after full information the PNH Service will support the patient in making decisions regarding pregnancy. It is therefore important to discuss the decision to become pregnant at the PNH clinic if at all possible. In almost all patients with PNH, pregnancy is potentially high risk and will be followed much more closely by both the local obstretric team in collaboration with the PNH Centre to prevent complications occurring and to reduce this risk. Treatment during pregnancy may include blood and platelet transfusions, folic acid, heparin (a drug to reduce the risk of developing blood clots) and eculizumab. During pregnancy it is important to be reviewed regularly both by haematology and obstetric specialists.

PNH FAQs

What test will I need to have to diagnose PNH?

PNH can be diagnosed through a simple blood test that is sent to the laboratory. Both PNH Centres also act as reference laboratories for diagnosis.

Will I have to have a Bone Marrow biopsy?

Due to the relationship of PNH and bone marrow failure, most commonly aplastic anaemia, it is likely that you will need to have a bone marrow biopsy at some point. The bone marrow is the organ (like a factory) of the body that produces the blood cells. Therefore, a bone marrow biopsy allows your medical team to see under the microscope a more detailed picture of your disease. There is much more information that we can gain from the bone marrow examination compared to the blood which can have an impact on the treatment required.

Will I need a Bone Marrow Transplant?

The treatment of PNH is decided on an individual patient basis and depends on the specific issues for that patient. For example, some patients are usually very well with only occasional episodes of symptoms whereas other patients suffer from haemolysis (rapid breakdown of PNH red cells) and anaemia with red or black urine or can have thrombosis as their main clinical problem. These are the classical symptoms of PNH and are not an indication for a bone marrow transplant. However if individual patients suffer mainly from bone marrow failure (e.g. severe aplastic anaemia or a weak bone marrow) then this may be an indication for a bone marrow transplant but this is relatively rarely necessary.

What does the PNH clone size mean?

PNH cells are not found in individuals without PNH or bone marrow failure and their detection is how we diagnose the disease. The machine that we use to detect PNH cells (called a flow cytometer) allows us to count the exact proportion of PNH cells compared to normal cells for all the blood cell types. We mainly concentrate on the white cells (neutrophils or granulocytes and monocytes) and on the red cells. The percentage of PNH granulocytes is usually the best way to assess the actual size of the PNH clone, as unlike red cells this is not affected by haemolysis (destruction of PNH red cells) or transfusions. The proportion of PNH granulocytes (or “PNH clone”) can vary in size from 0.01- 100% between different patients. The size of the PNH clone tends to have an impact on the symptoms an individual patient experiences but can be very variable.

Will my PNH clone always be the same size?

No, the PNH clone size can change over time with the number of PNH cells either staying stable, increasing or decreasing. For example we sometimes detect a small PNH clone in a patient with aplastic anaemia and this can over time increase in size so that the patient starts to experience symptoms of PNH. Most patients who have had PNH for a long period of time have relatively stable clone sizes although in some the clone can gradually reduce in size. In a small proportion of patients (less than 20% of patients in our experience) the clone can disappear altogether although this generally occurs over several years. It is not yet clear why some patients get better and there is nothing that we have found that predicts for which patient will improve.

How often will the size of my PNH clone be measured?

We will test the size of your PNH clone at most clinic visits. This allows us to monitor for any significant changes in your PNH and for us to consider any treatments that might be necessary to prevent complications.

Are my children at risk of getting PNH?

PNH is not an inherited condition (there is no increased risk in family members). PNH cannot be passed from one person to another.

If seen by the National PNH Service, do I still need to see my local haematologist?

The National PNH Service offers a shared care approach to managing your PNH but you still remain under the care of the local haematologist. It is therefore advisable that you continue to see your local haematologist. They will be looking after you should you become unwell and will often manage any problems separate to the PNH related to the underlying bone marrow failure, although we are happy to be involved as needed. The PNH Centre will work with your local haematologist to treat any problems that might arise related to your PNH but often the treatment will be delivered by your local team. Patients who are being treated with eculizumab need to be seen at least every 3 months either at a PNH Centre or an outreach clinic. Other patients will be seen in the PNH clinic as is necessary.

What can I do if I have further questions about my condition that I didn’t ask at my appointment?

It is not uncommon to either forget to ask a specific question during your consultation or to think of other questions that you want to ask about once you are back home. The National PNH Service are always happy to be contacted about you and your PNH. Please call the PNH service and ask to speak to one of the Clinical Nurse Specialists.